rs104894753

chrX-153906621-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_000054.7(AVPR2):c.1009C>T(p.Arg337Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: AVPR2 NM_000054.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.58

Genes affected

AVPR2 (HGNC:897): (arginine vasopressin receptor 2) This gene encodes the vasopressin receptor, type 2, also known as the V2 receptor, which belongs to the seven-transmembrane-domain G protein-coupled receptor (GPCR) superfamily, and couples to Gs thus stimulating adenylate cyclase. The subfamily that includes the V2 receptor, the V1a and V1b vasopressin receptors, the oxytocin receptor, and isotocin and mesotocin receptors in non-mammals, is well conserved, though several members signal via other G proteins. All bind similar cyclic nonapeptide hormones. The V2 receptor is expressed in the kidney tubule, predominantly in the distal convoluted tubule and collecting ducts, where its primary property is to respond to the pituitary hormone arginine vasopressin (AVP) by stimulating mechanisms that concentrate the urine and maintain water homeostasis in the organism. When the function of this gene is lost, the disease Nephrogenic Diabetes Insipidus (NDI) results. The V2 receptor is also expressed outside the kidney although its tissue localization is uncertain. When these 'extrarenal receptors' are stimulated by infusion of a V2 selective agonist (dDAVP), a variety of clotting factors are released into the bloodstream. The physiologic importance of this property is not known - its absence does not appear to be detrimental in NDI patients. The gene expression has also been described in fetal lung tissue and lung cancer associated with alternative splicing. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0959 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PP5: Variant X-153906621-C-T is Pathogenic according to our data. Variant chrX-153906621-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153906621-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AVPR2	NM_000054.7	c.1009C>T	p.Arg337Ter	stop_gained	4/4	ENST00000646375.2
AVPR2	NM_001146151.3	c.*185C>T		3_prime_UTR_variant	3/3
AVPR2	NR_027419.2	n.962C>T		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AVPR2	ENST00000646375.2	c.1009C>T	p.Arg337Ter	stop_gained	4/4		NM_000054.7	P1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1090434 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 357280

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 08, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects AVPR2 function (PMID: 9027323). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 10844). This variant is also known as R337stop. This premature translational stop signal has been observed in individuals with congenital nephrogenic diabetes insipidus (PMID: 8037205, 29594432, 34101133). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg337*) in the AVPR2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the AVPR2 protein. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2016	The R337X pathogenic variant in the AVPR2 gene has been reported previously in association with X-linked nephrogenic diabetes (Bichet et al., 1994; Boson et al., 2006; Boselt et al., 2012). This variant is predicted to cause loss of normal protein function through protein truncation. Functional studies indicate that cells expressing R337X have a significant decrease in cell surface expression compared to wild type (Wenkert et al., 1996). The R337X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R337X as a pathogenic variant. -

Diabetes insipidus, nephrogenic, X-linked Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	36
Dann	Uncertain	0.99
FATHMM_MKL	Benign	0.27	N
MutationTaster	Benign	1.0	A;A;A
Vest4		0.76
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104894753; hg19: chrX-153172075;